Moisturizers: Function, Formulation and Clinical Applications

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Chapter 14 Moisturizers: Function, Formulation and Clinical Applications

James Q. Del Rosso

INTRODUCTION

Dermatologists are commonly queried by patients regarding proper care of their skin. Specific questions may include ‘What cleanser should I use?’ or ‘What is the best sunscreen?’ or ‘Is there a specific moisturizer that you recommend?’ It is common for practitioners to select from an array of samples, or to become familiar with a few brand name products through personal familiarity or the random experiences of individual patients. In the past, decisions regarding selection of skin care products were arbitrary; however, as more scientific information on skin care formulations continues to emerge, clinicians are basing their recommendations more frequently on the science behind the formulations.

A thorough understanding of the features of moisturizer formulations, and their differences, provides the clinician with a greater ability to recommend products appropriately and confidently. Various factors related to formulation science impact on the type and extent of clinical benefit achieved and the potential for unwanted effects (i.e. skin irritation, lack of esthetic appeal).

Two basic processes that function in concert to maintain the overall health of skin are cleansing and moisturizing. Cleansing allows for removal of external debris, natural cutaneous secretions, and microorganisms. Moisturizers are an important component of basic skin care, especially in conditions where clinical or subclinical alteration of the epidermal barrier and/or reduced epidermal water content is present. Such conditions include low ambient humidity and clinically evident xerosis due to genetic tendency (e.g. ichthyosis) or underlying disease states (e.g. atopic dermatitis, hypothyroidism, diabetes), or use of products or medications associated with epidermal barrier disruption such as harsh cleansers, astringents, and some topical medications. The myriad of moisturizer products available confounds rational product selection. The bottom line is to maintain a ‘simplest is best approach’, especially as many product claims, special additives, and carefully marketed ‘prestige products’ are backed by little or no scientific evidence supporting their benefit or extraordinary expense.

This chapter reviews the fundamental principles related to formulating various types of moisturizer formulation and the current understanding of skin barrier physiology and function. Specific components of moisturizers, their functions, and resultant clinical effects are discussed.

MAINTENANCE OF NORMAL SKIN INTEGRITY AND WATER CONTENT

Cutaneous water balance, homeostasis, and normal skin appearance require the presence of an intact epidermal barrier. The epidermal barrier is composed of two functioning components: (1) a cellular protein matrix composed of an intertwined and layered lattice of keratinocytes (‘bricks’) with an uppermost layer of thin stratum corneum cells (corneocytes), and (2) an intercellular lipid bilayer matrix (‘mortar’). Proper function and maintenance of both components assures skin integrity, water balance, hydration, and orderly corneocyte desquamation. Disturb-ance of either of the epidermal components produces increased transepidermal water loss (TEWL), resulting in xerotic skin changes, characterized by dryness, scaling, roughness, fine fissuring, and associated pruritus. The ideal range of stratum corneum water content is 20–35%; reduction to below 10% water content results in visibly evident xerotic skin changes.

• Role of corneocytes and natural moisturizing factor

The epidermis is in constant flux, as corneocytes traverse from below and ultimately desquamate. In the presence of adequate water content, desquamation occurs upon enzymatic degradation of desmosomes, allowing for separation and shedding of superficial corneocytes. Unlike normal skin, xerotic skin is characterized by retained corneodesmosomes within desquamating stratum corneum, resulting in shedding of ‘clumps’ of corneocytes visibly apparent as flakes or scales, as opposed to imperceptible desquamation of single corneocyte cells. Stratum corneum chymotryptic enzyme activity, integral to the hydrolysis of corneodesmosomes and the physiologic process of desquamation, is reduced in soap-induced dry skin as compared to normal skin.

The moisture content of corneocytes is maintained by small hygroscopic compounds which have been collectively categorized under the term ‘natural moisturizing factor’ (NMF). The components of NMF include filaggrin-derived amino acids, pyrrolidone carboxylic acid (PCA), lactate, sugars, and several electrolytes (Box 14.1). If stratum corneum water content falls below a critical level, enzymatic function required for normal desquamation is impaired, leading to corneocyte adhesion and accumulation of corneocytes on the cutaneous surface. These aberrant changes correspond with the visible appearance of dryness, roughness, scaling, flaking, chafing, and fissuring.

Box 14.1 Chemical composition of natural moisturizing factor within corneocyte

CONCENTRATION > 5% CONCENTRATION < 5%

image Free amino acids

image Pyrrolidone carboxylic acid (PCA)

image Lactate

image Sugars

image Urea

image Chloride

image Sodium

image Ammonia

image Uric acid

image Glucosamine

image Creatine

image Calcium

image Magnesium

image Phosphate

image Citrate

image Formate

• Role of intercellular lipids

An important component of epidermal proliferation and differentiation is the formation of a permeability barrier composed of a programmed combination and ratio of lipids. Stratum corneum lipids are synthesized predominantly within the nucleated cells of the epidermis and are largely autonomous from circulating lipids. Lipid synthesis is regulated primarily by changes in epidermal barrier status. Epidermal barrier lipids are mostly composed of equimolar concentrations of free fatty acids, cholesterol, and ceramides. Lower quantities of cholesterol sulfate and nonpolar lipids are also present. The bipolar nature of lipids comprising the intercellular matrix allows for the formation of alternating lipid layers with hydrophilic ‘heads’ and hydrophobic ‘tails’. This orderly arrangement forms a barrier which controls water permeability and movement between epidermal cells (regulation of TEWL) and seals water-soluble hygroscopic compounds (NMF) within corneocytes, thus maintaining intracellular water content.

Epidermal lipids are also collected within lamellar bodies (Odland bodies) which are located within keratinocytes of the upper epidermis and function to biochemically convert newly synthesized lipids to an organized membrane structure (lamellar unit membrane structure). Lamellar bodies deliver proteolytic enzymes required for desquamation of corneocytes to the interstitium and convert ‘precursor lipids’ into vital barrier function lipids such as ceramides. As cornification occurs in the upper epidermis, a phospholipid-enriched plasma membrane is converted to a ceramide-rich bilayered membrane. At least seven subfractions of ceramides have been identified, accounting for up to 50% of stratum corneum lipid content by weight. Loss of epidermal lipids that are critical components of the lamellar epidermal barrier results in increased TEWL, a reduction in skin plasticity, and the adverse sequelae related to decreased stratum corneum water content as described above. Interestingly, significant reduction in multiple subfractions of ceramides has been noted in both lesional and nonlesional skin of patients with atopic dermatitis.

PHYSIOLOGIC EPIDERMAL BARRIER REPAIR

The homeostatic signal which correlates with maintenance and repair of epidermal barrier function is TEWL. When TEWL increases by as little as 1%, a physiologic signal initiates barrier repair by upregulating lipid synthesis. Disturbances in epidermal barrier permeability induce a physiologic response to restore barrier function, with normalization occurring within hours to days; the time course of restoration of barrier function is dependent on the extent of the insult, the age of the patient, and the patient’s overall health status. Recovery of the epidermal barrier occurs as extracellular lipids are secreted into the stratum corneum interstitium by keratinocytes underlying the site of insult and are organized into lamellar membrane unit structures. Within 30 minutes, lamellar bodies are deposited from the outer granular layer, followed within the next 4 hours by synthesis of fatty acids and cholesterol, and over the next 6–9 hours by increased ceramide production.

CLINICAL IMPACT OF MOISTURIZERS

In the presence of intrinsic or extrinsic factors that promote barrier disruption and reduced epidermal water content, moisturizers, especially those with optimized components, simulate the role of epidermal lipids in promoting and restoring epidermal barrier function. Externally applied lipids have been shown to intercalate between corneocytes and can mitigate surfactant-induced skin irritation. Application of nonphysiologic lipids such as petrolatum allows for restoration of barrier function by permeating within the interstitium of the stratum corneum and creating a diffuse hydrophobic phase.

Studies evaluating the application of physiologic lipids as moisturizers suggest that these lipids can be incorporated into the formation of barrier lipids and lamellar units and do not appear to downregulate physiologic lipid production in skin. However, based on in vitro murine models, the use of physiologic lipids in moisturizers appears to require the inclusion of all three lipid components (ceramide, cholesterol, free fatty acids) in optimized concentrations, otherwise barrier recovery may be impaired (Fig. 14.1).

image

Fig. 14.1 Physicians’ global assessment of improvement with a topical corticosteroid alone versus a moisturizer in combination with a topical corticosteroid

SIGNIFICANCE OF MOISTURIZER APPLICATION FREQUENCY

Due to the loss of applied product imposed by the continuous natural process of epidermal desquamation and limitations of product substantivity, persistent efficacy provided by moisturizer use requires repeated application on a daily basis.

Evaluation of moisturizing properties after discontinuation of treatment with moisturizers (regression phase analysis) has demonstrated longlasting effects for several days after use of both lanolin-based and cetyl alcohol/petrolatum/polyglycerylmethacrylate-based moisturizer preparations (Fig. 14.2).

image

Fig. 14.2 Regression analysis of selected moisturizing creams

SIGNIFICANT COMPONENTS OF MOISTURIZER FORMULATIONS

The ‘real world’ usage of a moisturizer formulation requires noticeable efficacy and cosmetic acceptability. With regard to efficacy, it is important to recognize that the term ‘moisturizer’ does not imply that moisture (water) is being added to the skin. Rather, a properly designed moisturizer formulation contains occlusive, humectant, and emollient ingredients.

image The occlusive component retards evaporation and water loss by forming a hydrophobic film on the skin surface and within the superficial interstitium between corneocytes.

image Humectant compounds attract water from the dermis and harbor water into the outer epidermal layer (‘from the inside out’). In climate conditions characterized by ambient humidity exceeding 70%, humectant compounds can also attract and trap water from the environment (‘from the outside in’). The combination of occlusive and humectant ingredients provides complementary actions in achieving and maintaining epidermal hydration and barrier function (Fig. 14.3).

image Emollient ingredients, described as being capable of ‘filling the crevices’ between fragmented collections of desquamating corneocytes, are the third major component of moisturizer formulations. Emollients contribute to clinical efficacy and cosmetic elegance by imparting a smooth, soft texture to the skin surface.

image

Fig. 14.3 Basic moisturizer components

• Occlusive ingredients

Occlusive agents are often greasy and are most effective when applied onto slightly dampened skin. Examples of occlusive ingredients include petrolatum, lanolin, mineral oil, and silicone derivatives (dimethicone, cyclomethicone) (Box 14.2). The use of lanolin is limited by odor, expense, and potential allergenicity. Mineral oil is frequently used due to its favorable texture (‘feel’), but is limited in its ability to reduce TEWL. The term ‘oil free’ implies that the formulation does not contain mineral or vegetable oils. Silicone derivatives are not greasy and when used alone impart a protective effect with limited moisturizing quality. They are often used in combination with petrolatum to impart a more cosmetically favorable texture as petrolatum alone is perceived by many consumers as ‘too greasy’.

Box 14.2 Occlusive agents

HYDROCARBON OILS/WAXES

image Petrolatum

image Mineral oil

image Paraffin

image Squalene

image Silicone derivatives:

Dimethicone
Cyclomethicone

FATTY ALCOHOLS

image Cetyl alcohol

image Stearyl alcohol

image Lanolin alcohol

FATTY ACIDS

image Stearic acid

image Lanolin acid

WAX ESTERS

image Lanolin

image Beeswax

image Stearyl stearate

VEGETABLE WAXES

image Carnauba

image Candelilla

PHOSPHOLIPIDS

image Lecithin

STEROLS

image Cholesterol

POLYHYDRIC ALCOHOLS

image Propylene glycol

• Humectant ingredients

Several compounds are added to moisturizers due to their humectant quality, attracting water from the dermis into the epidermis. Many humectant compounds also exhibit emollient properties when applied to skin. Examples of compounds that are commonly used in moisturizer formulations due to their humectant properties are listed in Box 14.3. It is important that a humectant agent when used as a moisturizer component be combined with an occlusive ingredient as application of a humectant alone can increase TEWL. For example, topical glycerin (glycerol) when applied alone to skin increases TEWL by 29%.

Box 14.3 Humectant agents

image Glycerin (glycerol)

image Honey

image Sodium lactate

image Ammonium lactate

image Urea

image Propylene glycol

image Sodium pyrrolidone carboxylic acid (sodium PCA)

image Hyaluronic acid

image Sorbitol

image Polyglycerylmethacrylate

image Panthenol

image Gelatin

• Emollient ingredients

Emollients are frequently ‘oily’ substances that include a vast array of compounds ranging from esters to long chain alcohols. Although emolliency does not necessarily correlate with reduction in TEWL, emollient characteristics do correlate with consumer satisfaction and product preference as a smooth skin texture is expected after moisturizer application. Examples of compounds with emollient properties are listed in Box 14.4. Some compounds may be used due to their emollient qualities and compatibility with other components used in specific formulations. Unlike astringent alcohols (e.g. isopropyl alcohol, ethyl alcohol), emollient alcohols (e.g. cetyl alcohol, stearyl alcohol) are non-drying and impart a smooth texture to skin upon application. Ester-type emollients include octyl stearate, isopropyl myristate, oleyl oleate, cetearyl isononanoate, and PEG-7 glyceryl cocoate. Depending on inherent properties, emollients may be classified as protective, fatting, astringent, or dry (Box 14.4).

Box 14.4 Compounds with emollient properties

PROTECTIVE EMOLLIENTS

image Diisopropyl dilinoleate

image Isopropyl isostearate

FATTING EMOLLIENTS

image Castor oil

image Propylene glycol

image Octyl stearate

image Glyceryl stearate

image Jojoba oil

ASTRINGENT EMOLLIENTS

image Dimethicone

image Cyclomethicone

image Isopropyl myristate

image Octyl octanoate

DRY EMOLLIENTS

image Isopropyl palmitate

image Decyl oleate

image Isostearyl alcohol

ESTHETIC CHARACTERISTICS AND SPECIAL MOISTURIZER ADDITIVES

• Formulation characteristics

The majority of moisturizers are formulated as lotions (oil-in-water emulsion) or creams (water-in-oil emulsion). Lotion formulations are thinner and are compatible with daytime facial use; characteristic basic components include mineral oil, propylene glycol, and water. Night creams and replenishing or ‘therapeutic’ formulations are composed of heavier lipids such as petrolatum or lanolin derivatives, mineral oil, and water. Correlation of specific formulations with ‘skin type’ is significant, as specified ingredient combinations are made more compatible with dry, normal, or oily complexions by adjusting oil : water ratios and the heaviness of occlusive ingredients and emollients. For example, dimethicone and cyclomethicone are nongreasy, noncomedogenic emollients that are commonly used in ‘oil-free’ facial moisturizers targeted for patients with ‘oily skin’. Oil-absorbent compounds such as talc or kaolin may be added to absorb excess sebum and reduce ‘facial shine’.

VEHICLE DELIVERY CHARACTERISTICS

Vehicle characteristics influence ingredient delivery, tolerability, and patient preference. Delivery may involve minor modifications of the formulation to accommodate a physical device such as a cloth or pad, with the physical characteristics of the device potentially influencing distribution of a moisturizer onto skin, and also cutaneous tolerability. Vehicle characteristics may contain ingredients in formulation ‘units’ such as the liposome, microsphere, or multivesicular emulsion. The multivesicular emulsion system (MVE) has been adapted to ceramide-based moisturizer and cleanser formulations, which may be designed to incorporate multiple independent active ingredients in concentric layers. MVE utilizes a two-phase oil-in-water emulsion system that incorporates multilamellar spheres of oil and water. The multilamellar system allows for controlled released of ingredients from their respective layers after application to skin. Importantly, the MVE moisturizer system has been shown to reduce TEWL and increase skin hydration.

THERAPEUTIC SIGNIFICANCE OF MOISTURIZER USE

Effective topical management of skin diseases such as acne vulgaris, rosacea, eczematous dermatitis, and psoriasis involves not only the selection of medications, but also the incorporation of appropriate skin care. Selection of a nonirritating cleanser formulation and a well-formulated moisturizer that is devoid of common irritants and allergens serves to reduce irritation that may be associated with topical medications (i.e. retinoids, benzoyl peroxide, calcineurin inhibitors) and also contributes independently to improvement of signs and symptoms of the underlying disease state. The latter has been demonstrated for disease states such as acne vulgaris, rosacea, and atopic dermatitis.

Use of a dermatologist-selected skin care system compared to self-selection of skin care products by patients has been shown to augment the reduction of signs and symptoms of rosacea, and to decrease the potential for skin irritation in patients undergoing topical treatment. Sequential application of a ceramide-based moisturizer before topical tazarotene has been shown to reduce irritation without a compromise in efficacy in the treatment of acne vulgaris. Importantly, it is not clear whether a moisturizer should be applied before or after a concomitantly used topical medication, as impact on efficacy may vary depending on formulation characteristics and/or the inherent properties of the active ingredients in the topical medication. Overall, more data are needed on sequential application of specific moisturizers and topical agents.

In the management of atopic dermatitis, gentle cleanser and moisturizer use has been shown to enhance the therapeutic benefit achieved with topical corticosteroid therapy. While topical corticosteroids effectively control exacerbations of eczematous dermatitis, the underlying problem of an impaired epidermal barrier is directly related to the pathophysiology of atopic dermatitis. Proper skin care is integral to the ‘every day management’ of atopic dermatitis, even when eczematous dermatitis is not visibly present, as maintenance of epidermal barrier integrity assists in reducing TEWL and diminishing flares.

CONCLUSION

As the primary goals of moisturizer use are to maintain skin integrity and appearance by retaining skin water content, preventing TEWL, and initiating barrier repair when cutaneous insult arises, the most important formulation ingredients are occlusive, humectant, and emollient components. Proper balancing of these components results in the development of clinically effective and cosmetically appealing formulations.

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